The present invention relates to a stereoselective tandem substitution and reduction reaction of 4-(cinalino) piperidine derivatives. The resulting 3,4-cis compounds are useful intermediates leading to intravenous analgesics.
U.S. Pat. No. 4,584,303 discloses a method of preparing compounds of the following formula: ##STR1## wherein R.sup.1 is a lower alkyl, lower cyclic alkyl, lower alkyl lower cyclic alkyl, lower alkenyl, lower alkyl phenyl; R.sup.2 is phenyl or aromatic heterocycle ring either of which may be substituted; and R.sup.3 may be a variety of groups including alkyl phenyl. With respect to the R.sup.1 and NHR.sup.2 substitutents, it is desirable to obtain the more pharmacologically active cis isomer.
The method taught in U.S. Pat. No. 3,584,303 for preparing compounds of formula (I) requires a multi-step synthetic route involving the preparation of cis isomers at an advanced stage of the synthetic route. Furthermore, a cis:trans ratio of not greater than 70:30 can be achieved.
J. Burke, Jr. et al., J. Med. Chem., Vol. 29, No. 6, pp 1087-1093 (1986), discloses a method to prepare piperidine derivatives, which method suffers the same disadvantages of the above-mentioned prior art method. Furthermore, the multi-step method of Burke et al. requires expensive starting materials and protection of the piperidine nitrogen.
The deprotonation of aliphatic imines followed by alkylation is generally known as, for example, shown by Collum et al., J. Am. Chem. Soc., Vol. 106, pp 4865-4869 (1984). The reduction of an imine is in itself also conventional.